Stuart M. Armstrong

Human Melatonin Suppression by Light is Intensity Dependent

Five intensities of artificial light were examined for the effect on nocturnal melatonin concentrations. Maximum suppression of melatonin following 1 hr of light at midnight was 71%, 67%, 44%, 38%, and 16% with intensities of 3,000, 1,000, 500, 350, and 200 lux (lx), respectively. In contrast to some previous reports, light of 1,000 lx intensity was sufficient to suppress melatonin to near daytime levels, and intensities down to 350 lx were shown to significantly suppress nocturnal melatonin levels below prelight values. On the basis of these data, it is suggested that when examining the melatonin sensitivity of patient groups (such as bipolar affective disorders) to artificial light, an appropriate light intensity should be established in each laboratory. Light of less intensity (e.g., 200–350 lx) may be more suitable to dichotomize patient groups from control subjects.

Entrainment of rat circadian rhythms by daily injection of melatonin depends upon the hypothalamic suprachiasmatic nuclei

Although pinealectomy has little effect on the generation of circadian rhythmicity by mammals, daily injections of the pineal hormone melatonin entrain free-running rats [30]. The present study was designed to determine if known components of mammalian circadian organization were necessary for melatonin entrainment. Rats received either lesions to the suprachiasmatic nuclei (SCN), sham-lesions or neurotoxic lesions to brain catecholamines or serotonin. They were then allowed to free-run in constant dim red light (DD) before each received daily injections of either 1 mg/kg melatonin or ethanol:saline vehicle for 90 days. They were allowed to free-run for 30 days afterwards. Rats which received sham-lesions or neurotoxic lesions entrained to melatonin injections but not to vehicle. Rats which received complete SCN lesions were unaffected by melatonin or vehicle. These data suggest that the behavioral effects of melatonin, like those on reproduction in seasonally breeding mammals, depend upon an intact circadian system and the SCN.

A chronometric approach to the study of feeding behavior

In many mammalian genera, the stimulus to feed is intimately associated with circadian rhythms. This stimulus arises from within the brain from biological time-keeping systems. Such a chronometric approach to feeding behavior follows from a consideration of the terrestrial mammals space-time pattern within the ecological niche. The ecological niche is a division of time as well as space. The restriction of certain behaviors to certain times of day and the concomitant evolution of nocturnality or diurnality represent strong advantages for survival in the wild. Experimental data, primarily from studies on the rat, in support of the chronometric approach, include: the reinstatement of cyclic feeding patterns after food deprivation; the continuation of circadian pattern of wheel running and nocturnal drinking during food deprivation; consideration of the ontogeny of the feeding pattern; the phenomenon of anticipatory appetite--the experimental demonstration that time of day can act as a conditioned stimulus for feeding; the evaluation of rhythms in digestion, absorption and assimilatory biochemical processes; the realization that many of these rhythms are not simply a consequence of the presence of food in the gut; the realization that the brain exerts considerable control over the peripheral rhythmic nutritional processes via ANS and endocrinological systems; and the fact that within the brain the SCN and structures well known to be involved in nutritional regulation, such as the VMH, LHA and monoamine systems, may all be involved in the circadian pattern of feeding. Further, the function of these neurological structures may be understood better by consideration of data from temporal changes in feeding patterns.

Evidence for a separate meal-associated oscillator in the rat

Three experiments were conducted to explore the relationship between food availability and the wheel running activity rhythms of intact rats. In two experiments re-entrainment when meal times were changed was studied. The rats showed an increase in activity immediately prior to a regular feeding time and this increase was more rapid when rats had been fed at that time in an earlier condition. Some evidence of transients at a former meal time was observed when the meal time was shifted to later in the day, but not when the meal time was shifted to earlier in the day. This led to the hypothesis that ad lib feeding masks rather than abolishes meal-entrained activity. In a third experiment, therefore, rats were entrained to a daily meal under a light-dark (LD) cycle, then placed in constant dark (DD) on ad lib food with occasional periods of deprivation. A burst of activity associated with the former meal time occurred during the deprivation period, but not during ad lib periods; it returned during subsequent deprivation. It is concluded that meal feeding entrains a separate oscillator with a period different from the oscillator entrained by the LD cycle.

Chronobiotics--drugs that shift rhythms.

A chronobiotic is defined and levels of action within the mammalian circadian pacemaker system, such as the retina, retinohypothalamic tract, geniculohypothalamic tract, suprachiasmatic nuclei, output and feedback systems are identified. Classes of drug that include the indoleamines, cholinergic agents, peptides, and benzodiazepines, which might act as chronobiotics within these levels, are evaluated. Particular emphasis is placed on the indole, melatonin (MLT). The clinical circumstances for use of chronobiotics in sleep disturbances of the circadian kind, such as jet lag, shift work, delayed sleep-phase syndrome, advanced sleep-phase syndrome, irregular and non-24-hr sleep-wake cycles, are described under reorganized headings of disorders of entrainment, partial entrainment, and desynchronization. Specific attention is given to the blind and the aged. Both human and animal studies suggest that MLT has powerful chronobiotic properties. MLT shows considerable promise as a prophylactic and therapeutic alternative or supplement to the use of natural and artificial bright light for resetting the circadian pacemaker. Throughout this discussion, the hypnotic and hypothermic versus the chronobiotic actions of MLT are raised. Finally, problems in the design of delivery systems for MLT are discussed.

Gender differences in the cortical electrophysiological processing of visual emotional stimuli

The processing of visual emotional stimuli has been investigated previously; however, gender differences in the processing of emotional stimuli remain to be clarified. The aim of the current study was to use steady-state probe topography (SSPT) to examine steady-state visually evoked potentials (SSVEPs) during the processing of pleasant and unpleasant images relative to neutral images, and to determine whether this processing differs between males and females. Thirty participants (15 males and 15 females) viewed 75 images low on the arousal dimension (categorised as pleasant, neutral or unpleasant) selected from the International Affective Picture System (IAPS), whilst a 13-Hz sinusoidal white visual flicker was superimposed over the visual field and brain electrical activity was recorded from 64 electrode sites. Results suggest that pleasant and unpleasant images relative to neutral images are associated with reductions in frontal latency and occipital amplitude. In addition, electrophysiological gender differences were observed despite there being no differences found between males and females on subjective mood or behavioural ratings of presented images (valence and arousal dimensions). The main gender difference reported in the current study related to the processing of unpleasant images (relative to neutral images) which is associated with widespread frontal latency reductions (predominantly right sided) in females but not in males. Our results suggest that gender differences do exist in the processing of visual emotional stimuli, and illustrate the importance of taking these differences into account during investigations of emotional processing. Finally, these gender differences may have implications for the pathophysiology of mood disorders such as depression.

Successful use of S20098 and melatonin in an animal model of delayed sleep-phase syndrome (DSPS)

In human delayed sleep-phase syndrome (DSPS), sleep onset and wake times occur far later than normal. In the population, DSPS may be an important contributor to complaints of sleep onset insomnia. We previously reported an animal model of DSPS in laboratory rats in which the onset of nocturnal activity is delayed by several hours [negative phase angle difference (PAD)]. The effect of melatonin 1 mg/kg SC and S20098 (Servier) 1 and 3 mg/kg on the negative PAD was investigated over 22 days of injections. In comparison to control injections of dimethylsulfoxide (DMSO), both melatonin and S20098 over approximately 9 days phase advanced the onset of activity toward the onset of darkness. At cessation of injections, activity onset delayed over approximately 11 days back toward, but as a group did not reach the original PAD. This effect of melatonin on the phase angle of entrained rats is consistent with its effects on delayed sleep in humans. It is likely, therefore, that S20098 may be of use to ameliorate DSPS in humans.

Dose dependent effects of S-20098, a melatonin agonist, on direction of re-entrainment of rat circadian activity rhythms.

The chronobiotic properties of melatonin are well documented. For example, following an 8-h phase advance of the light-dark cycle daily injections of melatonin administered at the pre-shift dark onset alter the direction of re-entrainment of rat activity rhythms. Using this 8-h phase advance paradigm, the effects of the melatonin agonist S-20098 (1 mg/kg and 3 mg/kg) on the rat circadian system were compared with those of melatonin. S-20098 altered the direction of reentrainment in the same manner as melatonin. A study using lower doses of S-20098 showed that the effect on direction of re-entrainment was dose-dependent, with 100% of rats responding at a dose of 100 µg/kg. S-20098 may, therefore, have therapeutic potential as a chronobiotic in the treatment of circadian disorders in humans.

Augmentation of serotonin enhances pleasant and suppresses unpleasant cortical electrophysiological responses to visual emotional stimuli in humans.

The serotonergic system is one of the major systems targeted in the pharmacological treatment of a wide range of mood disorders including depression; however, little is known about the neurophysiological mechanisms underlying the effects of serotonin (5-HT) on affective phenomena including emotional behaviours, mood and emotional processing. The aim of the current study was to investigate how 5-HT acutely modulates steady-state visually evoked potentials (SSVEP), heart rate (HR) and verbal ratings associated with the viewing of differently valent emotional images. In a randomised double-blind, placebo-controlled design, 17 healthy subjects were tested under two acute treatment conditions: placebo and citalopram (20 mg) (a selective serotonin re-uptake inhibitor, or SSRI). Participants were tested 2 h post treatment whilst viewing 75 images (categorised as pleasant, neutral or unpleasant). Results indicate that under placebo treatment, processing of unpleasant valence [unpleasant (-) neutral images] was associated with decreases in SSVEP amplitude and latency in frontal and occipital cortices, whereas processing of pleasant valence [pleasant (-) neutral images] was associated with amplitude decreases and latency increases within frontal and left temporoparietal cortices. Decreases in both amplitude and latency are both interpreted as surrogate measures of cortical activation or excitation. Citalopram relative to placebo attenuated the electrophysiological activation to unpleasant valence within frontal and occipital cortices, but potentiated electrophysiological activation (amplitude only) to pleasant valence within parietooccipital cortices. Citalopram relative to placebo also suppressed differences in heart rate associated with the viewing of pleasant and unpleasant images, but did not alter subjects subjective responses to emotional images. Results suggest that responsiveness to pleasant and unpleasant stimuli following neurochemical modulation may vary across different response systems (i.e. self-report, HR and SSVEP). Electrophysiological findings suggest that acute serotonergic augmentation with citalopram modulates cortical processing of emotionally valent stimuli such that response to pleasant valence is potentiated and response to unpleasant valence is suppressed. The findings suggest a possible neurophysiological mechanism underlying antidepressant drug action on emotion.

Overnight human plasma melatonin, Cortisol, prolactin, TSH, under conditions of normal sleep, sleep deprivation, and sleep recovery

Abstract: Early investigations of the effect of sleep deprivation on plasma melatonin reported no major changes. Recently, 36 hrs of sleep deprivation was reported to elevate melatonin levels on the post‐sleep deprivation night. Given these contradictions melatonin, Cortisol, prolactin, and thyroid stimulating hormone before, during, and, after sleep deprivation were examined in nine healthy young males following one night of sleep deprivation. Hormone levels at hourly intervals, for each night, were statistically analyzed by a repeated measures, two‐way factorial ANOVA. ANOVA was also performed for measures of area under the curve (AUC). No significant differences were observed for melatonin levels. Cortisol was significantly higher on the sleep deprivation night presumably reflecting the aroused state accompanying being awake; however, there were several time points on the control night when it was elevated also. Prolactin was higher on the post‐sleep deprivation and control nights but did not rise on the deprivation night, indicating a useful nonpolysomnographic index for discriminating overnight sleep and awake states. TSH levels showed a similar rise during the control and sleep deprivation nights, but remained flat on the post‐sleep deprivation night. It appears that the pineal is insulated against feedback from changes to the level of arousal accompanying sleep and wakefulness. In comparison, Cortisol, prolactin, and TSH levels vary with these states and are, therefore, useful indices of arousal and sleep‐wake.